title: Dengue virus modulates the unfolded protein response in a time-dependent manner.
abstract: Flaviviruses, such as dengue virus (DENV), depend on the host endoplasmic reticulum for translation, replication, and packaging of their genomes. Here we report that DENV-2 infection modulates the unfolded protein response in a time-dependent manner. We show that early DENV-2 infection triggers and then suppresses PERK-mediated eIF2α phosphorylation and that in mid and late DENV-2 infection, the IRE1-XBP1 and ATF6 pathways are activated, respectively. Activation of IRE1-XBP1 correlated with induction of downstream targets GRP78, CHOP, and GADD34. Furthermore, induction of CHOP did not induce apoptotic markers, such as suppression of anti-apoptotic protein Bcl-2, activation of caspase-9 or caspase-3, and cleavage of poly(ADP-ribose) polymerase. Finally, we show that DENV-2 replication is affected in PERK(-/-) and IRE1(-/-) mouse embryo fibroblasts when compared with wild-type mouse embryo fibroblasts. These results demonstrate that time-dependent activation of the unfolded protein response by DENV-2 can override inhibition of translation, prevent apoptosis, and prolong the viral life cycle.
authors.affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, and Graduate Group in Microbiology, Department of Plant and Microbial Biology, University of California, Berkeley, California 94720-7354, USA. jpena360@yahoo.com
authors.forename: José
authors.initials: J
authors.lastname: Peña
authors.forename: Eva
authors.initials: E
authors.lastname: Harris
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D003716:Dengue Virus / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000201:enzymology; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D054645:Protein Phosphatase 1 / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D053148:Caspase 3; D053453:Caspase 9; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D054645:Protein Phosphatase 1; D019253:Proto-Oncogene Proteins c-bcl-2; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497249:DDIT3 protein, human; C497250:Ddit3 protein, mouse; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C087519:PPP1R15A protein, human